The recent clinical success of antibody-drug conjugates has validated the benefits of combining macromolecule and small molecule therapeutics. Within this exciting area, a remaining challenge is to identify linker strategies that provide improved cleavage selectivity with site-specific drug delivery. An appealing solution would be to develop antibody-drug cleavage chemistry that relies on an external stimulus which can be applied in a site-specific fashion.
Light in the near-IR range (e.g., 650-900 nm) has unique potential in this context. These wavelengths exhibit significant tissue penetration, minimal toxicity, and, moreover, are clinically validated for both diagnostic and therapeutic applications. Near-IR fluorescence imaging is routine in certain clinical contexts and innovative applications, such as methods to optically define tumor margins during surgery, are being developed. Light-based therapeutic modalities using phototoxic small molecules have an extensive history in the treatment of cancer and skin disorders.
Existing approaches, however, rely on intracellular processes that use endogenous, often enzymatic, reactions with little inherent tumor selectivity. As a consequence, benign tissue uptake of the antibody through either antigen-specific or antigen-independent mechanisms can lead to off-target drug release with resulting dose-limiting toxicities, especially in organs responsible for catabolizing antibody-drug conjugates. Moreover, premature release in circulation can be a significant issue.